Spinal Muscular Atrophy (SMA) is an inherited neuromuscular disorder of the alpha motoneuron. The early onset forms are clearly inherited in an autosomal recessive pattern which are second in frequency to cystic fibrosis among heritable disorders affecting children. Later onset forms are more likely to follow an autosomal dominant pattern of inheritance. All SMA cases are characterized by symmetrical limb muscle weakness/atrophy, evidence of denervation, and anterior horn cell degeneration. The most severe form of SMA, Werdnig-Hoffmann disease (Acute SMA, or SMA type I), presents in the first months of life and is fatal by four years, if not earlier. Later onset cases generally have more benign phenotypes. For decades clinicians have debated over diagnostic criteria for the various forms of SMA, and whether they are the result of non-allelic mutations producing a common phenotype, or whether the SMAs are a monogenic disorder with variable phenotypic expression. In the past three years we have collected and "banked" over 500 transformed lymphocyte cell lines from SMA families. The SMA cell bank includes 4 multiple affected, 9 three affected, and 30 two affected chronic SMA families along with 8 consanguineous marriage Werdnig-Hoffmann families and several families with dominantly inherited late onset SMA. We have typed the most informative families with about 100 DNA markers and karyotyped chromosomes of 50 SMA patients as part of a gene mapping effort to locate the disease locus or loci which causes SMA. In this proposal we outline a strategy to genetically map the locus (loci) for all types of SMA including the genetically unavailing acute form(s), as well as a plan to evaluate genetic heterogeneity among SMA families. Molecular and genetic strategies are presented to focus and characterize the disease locus (loci) with the ultimate goal of identifying the abnormal gene product(s) responsible for Spinal Muscular Atrophy.